N-tritylimidazoles for treating fungal infections

ABSTRACT

Bis-imidazolyl-bisphenylmethane and pharmaceutically acceptable non-toxic salts thereof are useful as antimycotics especially against dermatomycosis caused by Trichophyton and Microsporium species and also against yeast infections of the skin and internal organs.

United States Patent Regel et al. Apr. 29, 1975 N-TRITYLIMIDAZOLES FORTREATING [58] Field of Search 424/273 FUNGAL INFECTIONS [75] Inventors:Erik K. Regel, [56] References Cited Wuppertal-Kronenberg; Karl-HeinzUNITED STATES PATENTS Buchel, Leverkusen; Manfred 3,073,841 1/1963Schindler 0; 260/309 P PP d. all of 3,321,366 5/1967 Mussell at al260/309 Germany OTHER PUBLICATIONS [73] Asslgnee' sa f gg g g gFournari. et al., Bul. Soc. Chirn. France, June, 1968,

upper 21 er e ermany pp. 24384446 [22] Filed: June 22, 1973 Tolkmith etal., Science, Vol. 158, pp. l462-l463.

[21] Appl. No.: 372,780

Primary Exammer-Jerome D. Goldberg Related US. Application Data [62]Division of Ser. No. l87,8l4. Oct. 8, l97l. Pat. No. [57] ABSTRACT3,824,310, which is a division of Ser. No. 873,098, OCL 31 1969B1s-1midazolyl-bisphenylmethane and pharmaceutlcally acceptablenon-toxic salts thereof are useful as [30] Foreign Application PriorityData antimycotics especially against dermatomycosis N 5 1968 G 1806995caused by Trichophyton and Microsporium species and crmmy 1 also againstyeast infections of the skin and internal 52 us. c1. .7 424/273 mgans[51 1 Int. Cl. H6lk 27/00 17 Claims, No Drawings N-TRITYLIMIDAZOLES FORTREATING FUNGAL INFECTIONS This application is a divisional of ourcopending application Ser. No. 187,814 filed Oct. 8, 1971 now US. Pat.No. 3,824,310, which is a divisional of our priorfiled application Ser.No. 873,098 filed Oct. 31, 1969.

The present invention is concerned withbis-imidazolyl-bisphenylmethanes, salts thereof, processes for theirproduction, pharmaceutical compositions containing such compounds andmethods of treating fungal infections pathogenic to humans and animalsand methods of treating yeast infections pathogenic to humans andanimals. More particularly, the compounds of the present invention arebis-imidazolyl-bisphenylmethanes which may be substituted in'one or bothof the imidazolyl moieties and one or both of the phenyl moieties.

The compounds of the present invention are particularly useful asantimycotics especially against dermatomycosis caused by triclwphytonand microsporium species and also against yeast infections of the skinand internal organs.

The compounds of the present invention may be represented by theformula:

R ii R3 -i R 1 cx I Y wherein R is hydrogen, alkyl, aryl or substitutedaryl,

R and R are the same or different and are hydrogen, alkyl, aryl,substituted aryl, or R and R together form a fused benzene ring,

X and y are the same or different and are an electronegative moiety,alkyl, S-alkyl or alkoxy,

m is 0, l or 2,

n is 0, l or 2,

and includes salts of such compounds.

When R, R or R is alkyl, it is preferred that the alkyl moiety containfrom 1 to 4 carbon atoms. When it is aryl, it is preferred that the arylmoiety contain up to carbon atoms in the ring system and the preferredaryl moiety is phenyl. The aryl may be substituted in which event thepreferred substituents are lower alkyl, S-alkyl or alkoxy, haloalkyl of1 to 4 carbon atoms in the alkyl portion and preferably 1 or 2 carbonatoms in the alkyl portion and wherein the halogen is preferablyfluorine, chlorine or bromine, or by an electronegative moiety,preferably a halogen.

When X or Y is alkyl, it is preferred that the alkyl moiety contain from1 to 12 carbon atoms and preferably l to 4 carbon atoms. when it isS-alkyl or alkoxy,

it is preferred that the alkyl portions contain from 1 to 4 carbonatoms. When it is an electronegative moiety, it is preferred that theelectronegative moiety be halogen, i.e., fluorine, chlorine, bromine oriodine, N0 CF or CN.

It is to be appreciated that when X or Yis more an one such moiety asabove defined, such as in the case where m or n is 2, that the moietiesmay be the some or different.

The term alkyl includes straight chain and branched chain alkyl moietiesas well as the saturated alkyl moieties and the partially unsaturatedmoieties, i.e., those containing a double bond.

The salts of the bis-imidazolyl-bisphenylmethanes of the presentinvention are preferably pharmaceutically acceptable non-toxic salts andexamples of acids which give salts useful as hereinabove discussedinclude the halogen hydracids, phosphoric acids, monoand bifunctionalcarboxylic acids and hydroxycarboxylic acids, for example, acetic acid,propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid,citric acid, salicylic acid, sorbic acid and lactic acid andl,5-naphthalene-di-sulphonic acid. Of particular interest are thehydrohalides, particularly the chlorides, lactates and salicylates ofthe bis-imidazolylbisphenylmethanes.

According to a preferred embodiment of the present invention, R, R and Rare hydrogen, X and Y are the same or different and are fluorine,chlorine, bromine, iodine, CN, N0 methoxy, thiomethyl or CF and m and nare l.

The bis-imidazolyl-bisphenylmethanes of the present invention may beproduced by reacting a diphenyldihalomethane of the formula:

wherein X, Y, m and n are as above defined and wherein Hal is chlorine,bromine or iodine, with the stoichiometric amount of and imidazolederivative of the formula:

azole derivative may be used: however, the corresponding quantity of oneof the conventional tertiary amines is preferably used, such astriethylamine, dimethylanilin, N,N-dimethyl-benzyl-amine and the like.

The starting materials used for the process of the present invention,i.e., the diphenyl-dihalomethanes of the formula (2) and the imidazolederivatives of the formula (3) are known or can be obtained according tomethods and/or procedures per se known.

The following examples are representative of compounds of the formula(2):

Diphenyldichloromethane 2-fluoro-diphenyldichloromethane3-fluoro-diphenyldichloromethane 4-fluoro-diphenyldichloromethane2-chlor0-diphenyldichloromethane 3-chlor0-diphenyldichloromethane4-chloro-diphenyldichloromethane 2-bromo-diphenyldichloromethane3-bromo-diphenyldichloromethane 4-bromo-diphenyldichloromethane2-nitro-diphenyldichloromethane 3-nitro-diphenyldichloromethane4-nitro-diphenyldichloromethane 2-cyano-diphenyldichloromethane3-cyano-diphenyldichloromethane 4-cyano-diphenyldichloromethane2-methyl-diphenyldichloromethane 3-methyl-diphenyldichloromethane4-methyl-diphenyldichloromethane 2-ethyl-diphenyldichloromethane3-ethyl-diphenyldichloromethane 4-ethyl-diphenyldichloromethane2-methoxy-diphenyldichloromethane 3-methoxy-diphenyldichloromethane4-methoxy-diphenyldichloromethane 2-methyl-thio-diphenyldichloromethane3-methyl-thio-diphenyldichloromethane4-methyl-thio-diphenyldichloromethane2-methyl-sulphinyl-diphenyldichloromethane3-methyl-sulphinyl-diphenyldichloromethane4-methyl-sulphinyl-diphenyldichloromethane2-methyl-sulphonyl-diphenyldichloromethane3-methyl-sulphonyl-diphenyldichloromethane4-methyl-sulphonyl-diphenyldichloromethane4-tert.butyldiphenyldichloromethane 4-phenyl-diphenyldichloromethane2,4-dichloro-diphenyldichloromethane2,5-dichloro-diphenyldichloromethane3,4-dichloro-diphenyldichloromethane4-chloro-2-nitro-diphenyldichloromethane4-chloro-3-nitro-diphenyldichloromethane6-chloro-3-nitro-diphenyldichloromethane2-chlor0-4-nitro-diphenyldichloromethane2,4-dinitro-diphenyldichloromethane 3,4-dinitro-diphenyldichloromethane3,5-dinitro-diphenyldichloromethane4-nitro-3-methyl-diphenyldichloromethane3-nitro-4-methyl-diphenyldichloromethane2,2'-difluoro-diphenyldichloromethane 2 ,3'-difluoro-diphenyldichloromethane 2,4'-difluoro-diphenyldichloromethane3,3'-difluor0-diphenyldichloromethane3,4'-difluoro-diphenyldichloromethane4,4-difluor-diphenyldichloromethane2-fluoro-2'-chl0ro-diphenyldichloromethane 2-fluoro-3-chloro-diphenyldichloromethane2-fluoro-4'-chloro-diphenyldichloromethane 3-fluoro-3'-chloro-diphenyldichloromethane3-fluoro-4'-chloro-diphenyldichloromethane4-fluoro-4'-chloro-diphenyldichloromethane4-fluoro-4'-bromo-diphenyldichloromethane2,2'-dichloro-diphenyldichloromethane 2,3'-dichl0ro-diphenyldichloromethane 2,4-dichloro-diphenyldichloromethane3,3'-dichloro-diphenyldichloromethane3,4-dichloro-diphenyldichloromethane4,4'-dichloro-diphenyldichloromethane2-chloro-4'-bromo-diphenyldichloromethane3-chloro-4-bromo-diphenyldichloromethane4-chloro-4'-bromo-diphenyldichloromethane4-fluoro-2'-nitro-diphenyldichloromethane4-fluor0-3'-nitro-diphenyldichloromethane4-fluoro-4-nitro-diphenyldichloromethane4-chloro-2'-nitro-diphenyldichloromethane 4-chloro-3-nitro-diphenyldichloromethane 4-ehloro-4'-nitro-diphenyldichloromethane4-bromo-2'-nitro-diphenyldichloromethane4-bromo-3'-nitro-diphenyldichloromethane4-bromo-4'-nitro-diphenyldichloromethane4-fluoro-4'-cyano-diphenyldichloromethane4-chloro-4'-cyano-diphenyldichloromethane4-bromo-4'-cyano-diphenyldichloromethane2-methyl-2'-fluoro-diphenyldichloromethane 2-methyl-3'-fluoro-diphenyldichloromethane2-methyl-4'-fluoro-diphenyldichloromethane2-methyl-2-chloro-diphenyldichloromethane 2-methyl-3'-chlor0-diphenyldichloromethane2-methyl-4'-chlor0-diphenyldichloromethane3-methyl-2'-fluoro-diphenyldichloromethane 3-methyl-3'-fluoro-diphenyldichloromethane3-methyl-4'-fluoro-diphenyldichloromethane3-methyl-2'-chloro-diphenyldichloromethane 3-methyl-3'-chloro-diphenyldichloromethane3-methyl-4'-chloro-diphenyldichloromethane4-methyl-2'-chloro-diphenyldichloromethane 4-methyl-3'-chlor0-diphenyldichloromethane4-methyl-4'-chloro-diphenyldichloromethane4-tert.-butyl-2'-fluoro-diphenyldichloromethane 4-tert.-butyl-3'-fluoro-diphenyldichloromethane4-tert.-butyl-4'-fluoro-diphenyldichloromethane4-tert.-butyl-2'-chloro-diphenyldichloromethane 4-tert.-butyl-3-chloro-diphenyldichloromethane4-tert.-butyl-4'-chloro-diphenyldichloromethane2,4-dichloro-2'-fluor0-diphenyldichloromethane 2,4-dichloro-3'-fluoro-diphenyldichloromethane2,4-dichloro-4'-fluoro-diphenyldichloromethane2,4-dichloro-2'-chloro-diphenyldichloromethane 2,4-dichloro-3-chloro-diphenyldichloromethane2,4-dichloro-4-chloro-diphenyldichloromethane2,5-dichloro-2'-fluoro-diphenyldichloromethane 2,5-dichloro-3'-fluoro-diphenyldichl0romethane2,5-dichloro-4'-fluoro-diphenyldichloromethane2,5-dichloro-2'-chloro-diphenyldichloromethane 2,5-dichloro-3'-chloro-diphenyldichloromethane2,5-dichloro-4'-chloro-diphenyldichloromethane 3 ,4-dichloro-2-fluoro-diphenyldichloromethane 3 ,4-dichloro-3'-fluor0-diphenyldichloromethane 3,4-dichloro-4'-fluoro-diphenyldichloromethane3,4-dichloro-2'-chloro-diphenyldichloromethane 3 ,4-dichloro-3'-chloro-diphenyldiehloromethane3,4-dichlor0-4'-chloro-diphenyldichloromethane4-chloro-2'-fluoro-2-nitro-diphenyldichloromethane 4-chloro-3'-fluoro-2-nitro-diphenyldichloromethane4-chloro-4-fluoro-2-nitro-diphenyldichloromethane4-chloro-2'-chloro-2-nitr0-diphenyldichloromethane 4-chloro-3'-chloro-2-nitro-diphenyldichloromethane4-chloro-4'-chloro-2-nitro-diphenyldichloromethane4-chloro-2'-fluoro-3-nitro-diphenyldichloromethane 4-chloro-3'-fluoro-3-nitro-diphenyldichloromethane4-chloro-4-fluoro-3-nitrodiphenyldichloromethane4-chloro-2'-chloro-3-nitro-diphenyldichloromethane 4-chloro-3'-chloro-3nitro-diphenyldichloromethane4-chloro-4'-chloro-3-nitro-diphenyldichloromethane6-chloro-4'-fluoro-3-nitro-diphenyldichloromethane6-chloro-4-chloro-3-nitro-diphenyldichloromethane2-chloro-4'-chloro-4-nitro-diphenyldichloromethane2-chloro-4'-fluoro-4-nitro-diphenyldichloromethane4-chloro-2',4'-dinitro-diphenyldichloromethane 4-chloro-3,4-dinitro-diphenyldichloromethane 4-chloro-3 ',5'-dinitro-diphenyldichloromethane4-chloro-3'-methyl-4-nitrodiphenyldichloromethane 4-chloro-4 -methyl-3-nitrodiphenyldichloromethane2,2,5,5'-tetrachloro-diphenyldichloromethane2-fluoro-4'-methoxy-diphenyldichloromethane 3 -fluoro-4'-methoxy-diphenyldichloromethane4-fluoro-4'-methoxy-diphenyldichloromethane2-chloro-4'-methoxy-diphenyldichloromethane3-chloro-4'-methoxy-diphenyldichloromethane4-chloro-4'-methoxy-diphenyldichloromethane2-methy1-4'-methoxy-diphenyldichloromethane3-methyl-4'-methoxy-diphenyldichloromethane4-methyl-4-methoxy-diphenyldichloromethane2-fluoro-4-methylthio-diphenyldichloromethane3-fluoro-4-methylthio-diphenyldichloromethane 4-fluoro-4'-methylthio-diphenyldichloromethane2-chloro-4-methylthio-diphenyldichloromethane3-chloro-4'-methylthio-diphenyldichloromethane4-chloro-4'-methy1thio-diphenyldichloromethane2,4-dichloro-4-methylthiodiphenyldichloromethane2,5-dichloro-4'-methylthiodiphenyldichlorom ethane3,4-dichloro-4'-methylthiodiphenyldichloromethane2,4-dichloro-4'-methoxy-diphenyldichloromethane2,5-dichloro-4'-methoxy-diphenyldichloromethane 3 ,4-dichloro-4'-methoxy-diphenyldichloromethane4-ethylthio-2-chloro-diphenyldichloromethane4-ethylsu1phonyl-2-chloro-diphenyldichloromethane The following examplesare representative of compounds of the formula (3);

imidazole 2-methylimidazole 2-ethylimidazole 2-phenylimidazole 4,(5)-phenylimidaz0le 4,5-diphenylimidazole benzimidazole Salts of compoundsof the formula (1 may be converted into their corresponding salts bytechniques per se known. For example, 0.2 mol of abis-imidazolylbisphenylmethane may be dissolved with heating inacetonitrile, followed by the addition of 0.22 ml D,L- lactic acid. Theresidue remaining after the solvent has been distilled off may be madeto crystallize by covering it, after filtration, with a layer of ether;the crystalline product may be washed with ether and dried.

The hydrochlorides are expediently obtained by introducing hydrogenchloride into the solution of the imidazole derivative, for example, incarbon tetrachloride.

there are added dropwise 55 g (0.21

The following table shows examples of the compounds of the invention:

a) bis-imidazolyl-bis-phenylmethane I b)bis-imidazolyl-4-chlorophenyl-phenylmethane I40 c)bis-imidazolyl-4-fluorophenyl-phenylmethane l 30 d)bis-imidazolyl-2,4'-difluoro-diphenylmethane 129 e)bis-imidazolyLZ-chlorophenyl-phenylmethane I43 f)bis-imidazolyl-3-chlorophenyl-phenylmethane 1 18 g)bis-imidazolyl-4-cyanophenyl-phenylmethane h) bis-( 2-methylimidazolyl)-4-chlorophenylphe'nylmethane 215 The compounds and salts of theformula (1) can be used, inter alia, in the form of an aqueous emulsion,suspension or solution. It is also possible to use the aqueous solutionsof the salts of the above compounds.

The invention is illustrated by the following Examples.

EXAMPLE 1 Bis-imidazolyl-4-chlorophenyl-phenylmethane To a solution of27.2 g (0.4 mol) imidazole and 40.4 g (0.4 mol) triethylamine in 300 mlacetonitrile there are added dropwise 54 g (0.2 mol) 4-chloropheny1-phenyl-dichloromethane. The triethylamine hydrochloride formed starts toseparate at room temperature. The mixture is heated at 80C for 12 hoursto complete the reaction. After cooling, the reaction mixture is stirredwith 500 ml benzene and washed with water until free of salt. Thebenzene solution is dried over anhydrous sodium sulphate, filtered andconcentrated by evaporation; after recrystallisation of the crude product from acetonitrile, there result 41 g of purebisimidazolyl-4-ch1orophenyl-phenylmethane of mp. C.

CIQHI5CIN4 mol. weight 334.5

Calculated: C. 68.0%; H 4.5%; Cl 10.6%; N 16.7%. Found: C, 68.0% H 4.8%;CI 10.7%; N 16.9%.

The same compound is obtained when, as starting compound, thedichloromethane compound is replaced by4-chlorophenyl-phenyl-dibromomethane or the corresponding diiodinecompound.

EXAMPLE 2 Bis-imidazolyl-4-fluorophenyl-phenylmethane Into a solution of29.4 g (0.43 mol) imidazole and 43.7 g (0.43 mol) triethylamine in 300ml acetonitrile mol) 4- C ll FN mol. weight 318 Calculated: C. 71.8%; H4.7%; F 6.0%; N l7.6%. Found: H 4.9%. F 6.0%. N 17.6%.

The following compounds of the formula (4) are prepared in a manneranalogous to that set forth in Example 2 by reacting the appropriatediphenyldichloromethane from the list on pages 7 to 12 with theappropriate imidazole set forth on page 12.

EXAMPLES 3 9 X m.p.C

4 5 3-Cl i11 6 4-CN 125 7 4Br 137 x 4 NO 163 8a 4-CH, O 122 8b 3-N0 4-Cl207 8c 3-N0 4--C1-1 166 8d 2.s c 140 9 4F 130 The following compounds ofthe formula (5) are prepared in a manner analogous to that set forth inExample 2 by reacting the appropriate diphenyldichloromethane from thelist on pages 7 to 12 with the appropriate imidazole set forth on page13.

EXAMPLES l0 15 1 It Y X Y m.p."C 10 2-F 4F 129 11 4F 4-4 I96 12 4F 4ClI83 13 4Cl 4Cl I98 14 4F 4N0z I98 15 4F 4-CN 190 The following compoundsof the formula (6) are prepared in a manner analogous to that set forthin Exampics 1 and 2 by reacting the appropriate diphenyldichloromethanefrom the list on pages 7 to 12 with the appropriate imidazole set forthon page 13.

EXAMPLES l6 34 THERAPEUTIC UTILITY l. Effectiveness in vitro againsthuman-pathogenic fungi II. In vivo activity Taking as example white miceinfected i.v. with Candida nlbicans and Aspergillus fumigatus, the newcompounds [e.g., (a) to (h)], given orally in doses of 50100 mg/kg bodyweight once or twice daily over 5 I days, show good curative effects.Dependent upon the dosage. the rate of survival of the animals thustreated amounted to 50 to percent, of the untreated control animals 0 tol0 percent.

With the same dosage scheme and a therapy duration of 8 to 10 days, thedevelopment of dermatomycoses caused by Trichophyton and Microsporiumspecies can be inhibited in mice and guinea pigs in an average of 70percent of the infected animals; in comparison with theuntreated-control group, the infection proceeds in the remaining 30percent mildly and adheres for only a short period of time.

The topical-therapeutic application in the form of ointments andtinctures with a 1 percent content of active ingredient leads in guineapigs infected with dermatophytes to healing of the mycosis within 6 to 8days post infection whereas in untreated control animals thedermatomycosis has an average duration of 28 to 31 days.

Similar results are obtained when, instead of the compounds (a) to (h),the other new compounds or salts are used.

Of special interest for practical use are the compounds which areunsubstituted on the imidazole ring, but which may be substituted in onephenyl moiety by a halogen atom (preferably chlorine, fluorine, in theo-, mor p-position, i.e., 2-, 3- or 4-position) as well as their saltswith hydrochloric acid, lactic acid or salicylic acid.

It is particularly envisaged that the compounds of the present inventionmay be used in the following manner; a. In human medicine:

1. Dermatomycoses caused by fungi of the species Trichvphyres,Microporium, Epidermophytes, Aepergillus, Candida albicans, and otheryeasts.

2. Organomycoses caused by yeasts, mould fungi and dermatophytes.

b. In veterinary medicine:

Dermatomycoses and Organomycoses caused by yeasts, mould fungi anddermatophytes. The therapeutical application can be effected orally orparenterally as well as topically in the form of solutions (e.g.,dimethyl sulphoxide/glycerol/water 222:6), alcohol, preferably ethanoland isopropanol, buffer solutions, powders, dreams, ointments andtablets. For topical application preferably a concentration of aboutfrom 0.5 to 10 percent of effective ingredient is used.

For humans the dosage amounts on average to between about 50 and about100 mg/kg body weight, preferably 50 to about 80 mg/kg body weight, atintervals of up to 12 hours for the duration of about 8 to about 10days.

However, it may of course be found desirable in some cases to deviatefrom the quantities indicated here, not only depending on the method ofapplication, but also on possible variations in individual reactions tothe compound or the kind of formulation and on the time or the intervalat which it is administered. It may thus be possible to manage with lessthan the abovementioned minimum amount in some cases, whereas in othercases the indicated upper limit may have to be exceeded. If largerquantities are administered, it may be advisable to distribute these inseveral individual doses over the day.

carriers, are the following: tablets, capsules, powders,

with sweetening additives and other conventional substances. Thetherapeutically active compound should generally be present at aconcentration of about 0.5 to per cent by weight of the total mixture,in quantities which are sufficient to achieve the dosage range mentionedabove.

For oral application, the tablets can obviously also contain additives,such as sodium citrate, calcium carbonate and dicalcium phosphatetogether with various other additives, such as starch, preferably potatostarch, and the like, and binding agents, such as polyvinyl-pyrrolidone,gelatin and the like. Lubricants, such as magnesium stearate, sodiumlauryl sulphate and talc may also be used concurrently for theproduction of the tablets. In the case of aqueous suspension and/orelixirs which are intended for oral use, the active substance may beprovided with various agents to improve the flavour, colouringsubstances, emulsifiers and/or with diluents, such as water, ethanol,propylene glycol, glycerol and similar compounds or combinations.

For parenteral application, solutions of the active substances in sesameor peanut oil, or in aqueous propylene glycol or N,N-dimethyl formamidecan be employed as well as sterile aqueous solutions in the case ofwater-soluble compounds. Aqueous solutions of this kind should bebuffered in the usual manner if necessary; furthermore, the liquiddiluent should be rendered isotonic from the start by the addition ofthe necessary amount of salt or glucose. Such aqueous solutions areparticularly suitable for intravenous, intramuscular and intraperitonealinjections.

Sterile aqueous media of this kind are prepared in known manner.

In mice, rats, rabbits, dogs and cats the LD of the compounds mentionedabove ranges from about 500 and 1,000 mg/kg body weight when orallyadministered.

The present invention also includes pharmaceutical compositionscomprising one or more compounds as hereinbefore described as the activeingredient in combination with a pharmaceutically acceptable non-toxicinert diluent or carrier.

The present invention further provides a medicament in unit dosage formwhich comprises at least one of the compounds hereinbefore describedeither alone or in combination with a pharmaceutically acceptable inertdiluent or carrier. The medicament may include a protective envelopecontaining the active compound and if used the diluent or carrier.

The term medicament in dosage unit form" as used in the presentspecification means as medicament as defined above in the fonn ofdiscrete portions each containing a unit dose, or a multiple orsub-multiple of a unit dose of the active compound or compounds. Suchportions may, for example, be in monolithic coherent form, such astablets, suppositories, pills or dragees; in wrapped or concealed form,such as wrapped powders, cachets, sachets, or capsules; in ampoules,either free or as a sterile solution suitable for parenteral injection;or in any other form known to the an.

Besides the antimycotic activity the compounds show an activity againstpathogenic protozoa, e.g., Trypanosoma, Trichomonas, Entamoebahistolytica, malaria parasites, Toxoplasma and against bacteria, e.g.,Staphylocci, Streptococci, Klebsiella, E. coli.

Further the compounds activate the granulation in wound healing and showa hypocholesterinaemic activity.

What is claimed:

1. A pharmaceutical composition in the form of a tablet, a capsule, apowder, a spray, a sterile aqueous suspension, an injectable solution,an elixir, a syrup or a suppository useful for treating fungalinfections pathogenic to humans or animals which comprises an antifungalamount of a compound of the formula wherein R is hydrogen or alkyl of lto 4 carbon atoms;

X and Y are alkyl of l to 4 carbon atoms; and

m is 0, l or 2, and

n is 0, l or 2; or a pharmaceutically acceptable non-toxic salt thereof,in combination with a pharmaceutically acceptable nontoxic inert diluentor carrier.

2. A pharmaceutical composition according to claim 1 wherein R ishydrogen.

3. A pharmaceutical composition according to claim2whereinmis0,lor2andnis1or2;ormislor2 and n is O, l or 2.

4. A pharmaceutical composition according to claim 1 wherein X and Y aremethyl.

5. A pharmaceutical composition according to claim 1 wherein R ishydrogen and m is and n is 0.

6. A pharmaceutical composition according to claim 1 in oraladministration form.

7. A pharmaceutical composition according to claim I in parenteraladministration form.

8. A pharmaceutical composition according to claim 1 in a form suitablefor topical application.

9. A method of treating fungal infections pathogenic to humans oranimals which comprises administering to a human or animal in need ofsaid treatment an antifungal amount of a compound of the formula R ishydrogen or alkyl of l to 4 carbon atoms;

X and Y are alkyl of l to 4 carbon atoms; and

m is 0, l or 2, and

n is O, l or 2; or a pharmaceutically acceptable non-toxic salt thereof.

10. A method according to claim 9 wherein R is hydrogen.

11. A method according to claim 10 wherein m is 0, l or2andnis lor2;ormis l or2andnis0, l or2.

12. A method according to claim 9 wherein X and Y are methyl.

13. A method according to claim 9 wherein R is hydrogen and m is 0 and nis 0.

14. A method according to claim 9 wherein said administration is indosage unit form.

15. A method according to claim 9 wherein said administration is oral.

16. A method according to claim 9 wherein said administration isparenteral.

17. A method according to claim 9 wherein said administration is bytopical application.

1. A PHARMACEUTICAL COMPOSITION IN THE FORM OF A TABLET, A CAPSULE, A POWDER, A SPRAY, A STERILE AQUEOUS SUSPENSION, AN INJECTABLE SOLUTION, AN ELIXIR, A SYRUP OR A SUPPOSITORY USEFUL FOR TREATING FUNGAL INFECTIONS PATHOGENIC TO HUMANS OR ANIMALS WHICH COMPRISES AN ANTIFUNGAL AMOUNT OF A COMPOUND OF THE FORMULA
 2. A pharmaceutical composition according to claim 1 wherein R1 is hydrogen.
 3. A pharmaceutical composition according to claim 2 wherein m is 0, 1 or 2 and n is 1 or 2; or m is 1 or 2 and n is 0, 1 or
 2. 4. A pharmaceutical composition according to claim 1 wherein X and Y are methyl.
 5. A pharmaceutical composition according to claim 1 wherein R1 is hydrogen and m is 0 and n is
 0. 6. A pharmaceutical composition according to claim 1 in oral administration form.
 7. A pharmaceutical composition according to claim 1 in parenteral administration form.
 8. A pharmaceutical composition according to claim 1 in a form suitable for topical application.
 9. A method of treating fungal infections pathogenic to humans or animals which comprises administering to a human or animal in need of said treatment an antifungal amount of a compound of the formula
 10. A method according to claim 9 wherein R1 is hydrogen.
 11. A method according to claim 10 wherein m is 0, 1 or 2 and n is 1 or 2; or m is 1 or 2 and n is 0, 1 or
 2. 12. A method according to claim 9 wherein X and Y are methyl.
 13. A method according to claim 9 wherein R1 is hydrogen and m is 0 and n is
 0. 14. A method according to claim 9 wherein said administration is in dosage unit form.
 15. A method according to claim 9 wherein said administration is oral.
 16. A method according to claim 9 wherein said administration is parenteral.
 17. A method according to claim 9 wherein said administration is by topical application. 